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EP3908273B1 - Méthode et dispositif associé pour la conversion de cbd en thc - Google Patents

Méthode et dispositif associé pour la conversion de cbd en thc Download PDF

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Publication number
EP3908273B1
EP3908273B1 EP20738382.9A EP20738382A EP3908273B1 EP 3908273 B1 EP3908273 B1 EP 3908273B1 EP 20738382 A EP20738382 A EP 20738382A EP 3908273 B1 EP3908273 B1 EP 3908273B1
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Prior art keywords
thc
cbd
acidicly
enriched
solid support
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German (de)
English (en)
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EP3908273A1 (fr
EP3908273A4 (fr
EP3908273C0 (fr
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Alex Nivorozhkin
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Arielium Health LLC
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Arielium Health LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
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    • B01J8/02—Chemical or physical processes in general, conducted in the presence of fluids and solid particles; Apparatus for such processes with stationary particles, e.g. in fixed beds
    • B01J8/0285—Heating or cooling the reactor
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24F—SMOKERS' REQUISITES; MATCH BOXES; SIMULATED SMOKING DEVICES
    • A24F42/00—Simulated smoking devices other than electrically operated; Component parts thereof; Manufacture or testing thereof
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    • A—HUMAN NECESSITIES
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    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/04—Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised
    • A61M11/041—Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised using heaters
    • A61M11/042—Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised using heaters electrical
    • A—HUMAN NECESSITIES
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    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
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Definitions

  • the predominantly occurring cannabinoids in cannabis plant material are in fact (-)-trans- ⁇ 9 -THC and (-)-trans- ⁇ 1 -CBD.
  • THC tetrahydrocannabinol
  • CBD cannabidiol
  • (-)-trans - ⁇ 8 -THC is also routinely detected in plant isolates, though in small quantities, and is oft subsumed within the category of THC.
  • Such naturally occurring compounds have been suggested for use in treatment of an evergrowing list of medical conditions, including epilepsy, pain, inflammation, anxiety reduction, sleep improvement, multiple sclerosis, neuropathic pain, spasticity, overactive bladder, antiemesis, and appetite stimulation. Others have found these compounds to be indicated for recreational use related to certain of their psychoactive properties. In either case, these compounds have become of major pharmacological interest in the last 20 years.
  • US 2010/210860 discloses a method for the preparation of dronabinol ( ⁇ 9 - THC) from cannabidiol (CBD) by cyclization of cannabidiol (CBD). Given this lack of success in chemical synthesis of THC, commercial production of THC has been generally relegated to enhancements of isolation techniques and plant based engineering for extraction of the natural product.
  • the present invention is directed to methods of producing THC from CBD utilizing non-harsh methodology and resulting in substantially increased yields, as well as devices built upon these novel methods.
  • the methods and devices are material efficient, and in certain embodiments, solvent-free.
  • these methods and related devices are suitable for commercial production of THC from CBD.
  • the present invention provides methods of producing THC from CBD in manner that affords tunability to select the ratio of THC-8 to THC-9.
  • one aspect of the present invention provides a material-efficient method for conversion of cannabidiol (CBD) to tetrahydrocannabinol (THC).
  • CBD cannabidiol
  • THC tetrahydrocannabinol
  • CBD cannabidiol
  • THC tetrahydrocannabinol
  • CBD cannabidiol
  • THC tetrahydrocannabinol
  • Yet another aspect of the present invention provides a tetrahydrocannabinol (THC) production device comprising: a vessel for containing acidicly enriched solid support particles; and a plurality of CBD-activated acidicly enriched solid support particles positioned inside the vessel, wherein THC is produced from the CBD-activated acidicly enriched solid support particles, wherein the acidicly enriched solid support particles are comprising acid functional groups that are covalently linked to the solid support.
  • THC tetrahydrocannabinol
  • Still yet another aspect of the present invention provides a tunable tetrahydrocannabinol (THC) production device comprising: a vessel for containing acidicly enriched solid support particles; and a plurality of acidicly enriched solid support particles positioned inside the vessel, wherein THC is produced from the CBD-activated acidicly enriched solid support particles.
  • THC tetrahydrocannabinol
  • THC tetrahydrocannabinol
  • Figure 1 depicts an (A) HPLC trace of the reaction product from the Amberlyst-15-catalyzed CBD to THC transformation (heptane, reflux 45 min); and (B) HPLC trace of the reaction mixture from the Amberlyst-15-catalyzed CBD to THC transformation (heptane, ambient temperature, 2 h).
  • the peak assignment as following: CBD (RT 5.41 min), (-) ⁇ 9 -THC (RT 7.76 min), (-) ⁇ 8 -THC (RT 7.99 min).
  • the present invention is directed to methods and related devices for use in conversion of cannabidiol (CBD) (e.g ., and simple derivatives thereof) to tetrahydrocannabinol (THC) ( e.g., and simple derivatives thereof).
  • CBD cannabidiol
  • THC tetrahydrocannabinol
  • Both CBD and THC have two carbon stereo- centers that give rise to four diastereomers, (-)- cis -, (+)- cis -, (-)- trans -, and (+)- cis - .
  • the natureselected ones, and more potent psychoactive compounds, are those with (-)- trans- configuration.
  • CBD and THC are as follows: Positional isomerization of the vinyl group in the CBD carbocycle leads to ⁇ 9 -, ⁇ 8 - for THC, where the ⁇ 8 - THC is putatively regarded as thermodynamically more stable than ⁇ 9 - THC. Moreover, for convenience, ⁇ 9 -THC is referred to herein as THC-9, and ⁇ 8 -THC is referred to herein as THC-8.
  • the present invention utilizes acidicly enriched solid support particles with no additional catalytic molecules, e.g ., no additional acidic catalytic agents in the methods and devices of the present invention, beyond the acidicly enriched solid support particles (no further acid added to reaction other than solid support is required for conversion).
  • the method utilizes the introduction of CBD to the acidicly enriched solid support particles to create a CBD-activated accelerated conversion environment in order to convert the CBD to THC in a one-step process.
  • the resulting THC is therefore produced from the one step conversion and the product isolation is achieved simply by a removal of the solid support particles.
  • the process and related devices avoid harsh solvent conditions and are completed within a substantially reduced time frame (e.g ., compressed time frame), producing high levels of conversion of CBD (i.e., the conversion reactions go to completion or near completion) with very clean crude reaction product, including low (to no) residual solvent contamination.
  • the processes and devices of the present invention of the invention are therefore material efficient and commercially relevant.
  • the increased rates of reaction afford the devices of the present invention the ability to take numerous convenient forms, e.g ., commercially convenient, including those that afford flow adaptions to CBD isolation systems.
  • the THC ratio i.e., between THC-9 and THC-8
  • this ratio may be selectively produced as a single product or ratio of multiple products, e.g ., including starting material CBD).
  • the present invention is directed to methods of producing THC from CBD utilizing non-harsh methodology and resulting in substantially increased yields, as well as devices built upon these novel methods.
  • the methods and devices are material efficient, and in certain embodiments, solvent-free.
  • these methods and related devices are suitable for commercial production of THC from CBD.
  • the present invention provides methods of producing THC from CBD in manner that affords tunability to select the ratio of THC-8 to THC-9.
  • accelerated conversion environment is used herein to describe the reaction environment that enhances and accelerates conversion of the CBD to THC created by the use of the acidicly enriched solid support particles of the present invention.
  • enhancement and acceleration is relative to existing solution phase chemistry conversion of CBD to THC, and includes, for example, enhanced conversion efficiency of CBD, increased purity, e.g ., of crude reaction, increased rate of production of THC, increased yield of production of THC, any combination thereof.
  • acidicly enriched as used in the language “acidicly enriched solid support particles” is used herein to describe the functionalization of the solid support particles of the present invention, i.e ., the functional groups that are covalently linked to the support particles.
  • Such functional groups must be suitable to achieve residual level acidity (i.e., comprising suitable Lewis or Br ⁇ nsted acid functional groups) to support the acidic catalysis of a reaction, i.e., the conversion of CBD to THC.
  • This residual level of acidity is a characteristic of the functional groups covalently bound to the solid support particles, and is distinct from the addition of solution phase acid, e.g ., in situ or in a pre-conditioning step.
  • CBD-activated is used herein to describe the presence of CBD, wherein the CBD has been introduced into or onto a material, e.g ., on the acidicly enriched solid support particles of the present invention affording a CBD-activated accelerated conversion environment.
  • introduction or "introducing” is used herein to describe the non-covalent addition of one material, e.g ., CBD, to another material, .e.g., solid support particles.
  • material-efficient is used herein to describe methods/processes that reduce reaction conditions/reagents to reduce waste (as compared to existing methods/processes or in an absolute fashion when certain conditions/reagents are eliminated entirely), and therefore afford commercially relevant methods/devices such as those provided in the present invention.
  • the use of the acidicly enriched support particles eliminates the need for harsh solvents and solution based acid catalysts, and are therefore material-efficient.
  • the reduced time frame is used herein to describe the reduction in the time window in which a reaction proceeds, e.g ., the CBD to THC conversion, as compared to existing/known reactions.
  • the reduced time frame is a "compressed time frame” that describes a reaction that is complete within 1 min to 3 hours, e.g ., 1 min to 2 hours, e.g., 1 min to 1 hours, e.g., 1 min to 30 min, e.g., 1 min to 20 min, e.g., 1 min to 15 min, e.g., 1 min to 10 min, e.g., 1 min to 5 min, e.g., less than 5 min.
  • solid support particles is used herein to describe solid particles used for non-covalent reaction support.
  • the present invention utilizes solid support particles that are acidicly enriched.
  • the acidicly enriched support particles are selected from the group consisting of acidicly enriched resin beads (e.g ., Amberlyst-15 resin beads, Nafion particles), acidicly enriched functionalized silica gel (e.g ., silica supported sulfonic and phosphoric acids), acidicly enriched zirconium oxide, acidicly enriched aluminosilicate zeolites, acidicly enriched aluminophosposilicate zeolites, and any combination thereof.
  • acidicly enriched resin beads e.g ., Amberlyst-15 resin beads, Nafion particles
  • acidicly enriched functionalized silica gel e.g ., silica supported sulfonic and phosphoric acids
  • acidicly enriched zirconium oxide e.g ., acidicly
  • THC tetrahydrocannabinol
  • THC-9 is used herein as a representative notation for ⁇ 9 -THC” or "THC-delta-9.”
  • THC-8 is used herein as a representative notation for ⁇ 8 -THC” or “THC-delta-8.” This isoform has been found to be close in potency (at the cannabinoid CB1 and CB2 receptors and in human clinical trials) to (-)- trans - ⁇ 9 -THC (Hollister, 1974; Hanus, 2016).
  • tunable is used herein to describe the ability to tune to, or select, a given product or product ratio by selecting additional factors for the method used or method-reliant device, such as, for example, selecting the acidicly enriched solid support particles, selecting the temperature, selecting the time of reaction before extraction, selecting the particular solvent, or any combination thereof.
  • zeolite as used in the present invention to describe solid support particles of the present invention comprising any member of the family of hydrated aluminosilicate minerals that contain alkali and alkaline-earth metals.
  • the zeolites have a well-known three-dimensional tetrahedral framework structure wherein each oxygen atom is shared by two tetrahedral, and which encloses interconnected cavities, e.g ., having diameters ranging from about 2 to 8 angstroms, typically occupied by large metal cations (positively charged ions) and water molecules.
  • these metal ions are typically mono- or di-valent ions such as sodium, potassium, magnesium, calcium, and barium.
  • the acidicly enriched solid support particles utilized in the methods and devices of the present invention are functionalized with hydrogen in replacement of these metal cations suitably to achieve residual level acidity.
  • CBD may converted into THC by introduction to support particles that are acidicly enriched.
  • the introduction of the CBD to the acidicly enriched solid support particles creates a CBD-activated accelerated conversion environment.
  • the CBD may comprise additional functional groups in accordance with the well-known cannabinoid art, i.e., simple derivatives, which in turn may produce simple derivatives of THC as the final product rather than THC.
  • the methods are material-efficient, tunable, and may be solvent-free in certain embodiments.
  • one embodiment of the present invention provides a material-efficient method for conversion of cannabidiol (CBD) (e.g. , and simple derivatives thereof) to tetrahydrocannabinol (THC) (e.g., and simple derivatives thereof) comprising the step of: introducing CBD to acidicly enriched solid support particles to create a CBD-activated accelerated conversion environment, such that THC (e.g., and simple derivatives thereof) is produced.
  • CBD cannabidiol
  • THC tetrahydrocannabinol
  • Another embodiment of the present invention provides a tunable material-efficient method for conversion of cannabidiol (CBD) (e.g., and simple derivatives thereof) to tetrahydrocannabinol (THC) (e.g., and simple derivatives thereof) comprising the step of: introducing CBD to acidicly enriched solid support particles to create a CBD-activated accelerated conversion environment, such that THC ( e.g., and simple derivatives thereof) is selectively produced in the accelerated conversion environment ( e.g ., by selecting the acidicly enriched solid support particles, selecting temperature, selecting time of reaction before extraction).
  • the THC e.g., and simple derivatives thereof
  • the THC is selectively produced as a single product or ratio of multiple products, e.g ., including starting material CBD.
  • Yet another embodiment of the present invention provides a solvent-free method for conversion of cannabidiol (CBD) (e.g., and simple derivatives thereof) to tetrahydrocannabinol (THC) ( e.g., and simple derivatives thereof) comprising the step of: introducing CBD to acidicly enriched solid support particles through direct melt of the CBD to create a CBD-activated accelerated conversion environment, such that THC ( e.g., and simple derivatives thereof) is produced.
  • CBD cannabidiol
  • THC tetrahydrocannabinol
  • Another embodiment of the present invention provides a material-efficient method for conversion of THC-9 ( e.g., and simple derivatives thereof) to THC-8 ( e.g., and simple derivatives thereof) comprising the step of: introducing THC-9 to acidicly enriched solid support particles to create a THC-9-activated accelerated conversion environment, such that THC-8 ( e.g., and simple derivatives thereof) is produced.
  • Certain embodiments of the methods of present invention further comprise the step of heating said CBD-activated accelerated conversion environment.
  • the accelerated conversion environment is heated to less than or equal to 100 °C.
  • the acidicly enriched solid support particles are used less than 50%, e.g., less than 40%, e.g., less than 30%, e.g., less than 20%, e.g ., less than 10%, by weight ratio with respect to the CBD.
  • the acidicly enriched solid support particles are used in at least 10% by weight ratio with respect to the CBD.
  • the step of introducing the CBD to the acidicly enriched solid support particles is through solvent dissolution (e.g ., using a hydrocarbon solvent or an oil, e.g ., natural or synthetic) of the CBD to create the CBD-activated accelerated conversion environment.
  • the solvent may be recovered following conversion, supporting a more renewable "green" process.
  • the isolation/separation of the THC produced may be achieved by separation of the reaction solvent from the acidicly enriched solid support particles, e.g ., without additional reaction workup. In particular embodiments, this separation may be through additional solvent extraction, e.g ., solvent washing of the particles to recover THC produced.
  • the step of introducing the CBD to the acidicly enriched solid support particles is through solvent-free direct melt of the CBD to create the CBD-activated accelerated conversion environment.
  • the acidicly enriched solid support particles are used at a 50% by weight ratio with respect to the CBD.
  • Such direct melt processing capitalizes on the low melting point of CBD (m.p. 66 °C) and occurrence of THC as oil.
  • the acidicly enriched solid support particles also serve as a filtration/separation mechanism, i.e ., THC impurities/side-products remain behind after solvent washing of the particles to recover the THC produced in the melt on the particles.
  • THC produced is greater than 90% pure THC.
  • the solvent-free melt method increases the reaction speed as compared with non-melt (solvent based) conditions.
  • Certain embodiments of the methods of present invention further comprise the step of extraction of the solid support particles (e.g ., using an appropriate solvent, e.g., a hydrocarbon solvent, an alcohol, or a plant oil).
  • an appropriate solvent e.g., a hydrocarbon solvent, an alcohol, or a plant oil.
  • the THC produced in the accelerated conversion environment is selected from the group consisting of THC-9, THC-8, and any combination or ratio thereof.
  • the THC is tunable, or selectively produced in the accelerated conversion environment.
  • the selectivity is the result of selecting the acidicly enriched solid support particles, selecting temperature, selecting time of reaction before extraction, selecting a particular solvent, or any combination thereof.
  • the selectively is produced as a single product or ratio of multiple products, e.g ., including starting material CBD.
  • the THC produced in the accelerated conversion environment has a THC-9 bias (e.g., greater than 50%, e.g., greater than 60%, e.g., greater than 70%, e.g., greater than 80%, e.g., greater than 90%).
  • the THC produced in the accelerated conversion environment has a THC-8 bias (e.g ., greater than 50%, e.g., greater than 60%, e.g., greater than 70%, e.g., greater than 80%, e.g., greater than 90%).
  • a THC-8 bias e.g ., greater than 50%, e.g., greater than 60%, e.g., greater than 70%, e.g., greater than 80%, e.g., greater than 90%).
  • the THC produced in the accelerated conversion environment is produced with enhanced conversion efficiency of the CBD (i.e., consumption of CBD) with greater than 75% efficiency (e.g. , greater than 80% efficiency, e.g., greater than 85% efficiency, e.g., greater than 90% efficiency, e.g., greater than 95% efficiency).
  • the THC produced in the accelerated conversion environment is greater than 50% pure (e.g., greater than 60% pure, e.g., greater than 70% pure, e.g., greater than 75% pure).
  • the THC produced in the accelerated conversion environment is greater than 80% pure (e.g., greater than 85% pure, e.g., greater than 90% pure, e.g., greater than 95% pure).
  • the THC produced in the accelerated conversion environment is produced at an enhanced rate (e.g ., less than or equal to 3 hours, e.g., less than or equal to 2 hours, less than or equal to 1 hour, e.g., less than or equal to 45 min, e.g., less than or equal to 30 min, e.g., less than or equal to 20 min, e.g., less than or equal to 15 min, e.g., less than or equal to 10 min, e.g., less than or equal to 5 min).
  • an enhanced rate e.g ., less than or equal to 3 hours, e.g., less than or equal to 2 hours, less than or equal to 1 hour, e.g., less than or equal to 45 min, e.g., less than or equal to 30 min, e.g., less than or equal to 20 min, e.g., less than or equal to 15 min, e.g., less than or equal to 10 min, e.g.
  • the THC produced in the accelerated conversion environment is 50 g or greater ( e.g., 100 g or greater, e.g., 250 g or greater).
  • the THC produced in the accelerated conversion environment is 500 g or greater (e.g., 1 kg or greater, e.g., 5 kg or greater, e.g., 10 kg or greater, e.g., 20 kg or greater, e.g., 100 kg or greater, e.g., 500 kg or greater).
  • the solid support particles are selected from the group consisting of acidicly enriched polymer resin beads (e.g ., Amberlyst-15 resin beads, Nafion particles), acidicly enriched functionalized silica gel (e.g ., silica supported sulfonic and phosphoric acids), acidicly enriched zirconium oxide, acidicly enriched aluminosilicate zeolites, acidicly enriched aluminophosposilicate zeolites, and any combination thereof.
  • acidicly enriched polymer resin beads e.g ., Amberlyst-15 resin beads, Nafion particles
  • acidicly enriched functionalized silica gel e.g ., silica supported sulfonic and phosphoric acids
  • acidicly enriched zirconium oxide e.g ., acidicly enriched aluminosilicate zeolites, acidicly enriched aluminophosposilicate zeolites, and any combination thereof.
  • the solid support particles are selected for additional properties, e.g ., related to use of the final THC product, and include, for example, to avoid leaching.
  • the solid support particles are selected based on the hydrolytic stability, e.g ., related to the linker to the acid functionality. In particular embodiments, this results in a reduction of sensitivity to moisture.
  • the acidicly enriched solid support particles are renewable, i.e., may be used again, supporting a more renewable “green” process.
  • the acidicly enriched solid support particles are support particles of an ion-exchange type, e.g ., such as AMBERLYST-15 or 35 resins that are available in a bead form.
  • These support particles are acidic, e.g ., strongly acidic, ion exchange styrene-divinylbenzene polymeric scaffold containing sulfonic acid moieties (5-6 eqv/kg) and developed for binding of cationic impurities in chromatography, purification and other applications.
  • AMBERLYST 15 and 35 permits ready access of reactants to the hydrogen ion sites located throughout the bead, thus facilitating successful performance even in non-swelling organic media.
  • the acidicly enriched solid support particles are support particles of an active ion-exchange acidic catalyst, such as Nafion-H ® , a sulfonated polymer prepared by polymerization of perfluorinated vinyls and perfluorinated vinyl esters, tetrafluoro-ethylene-perfluoro-3,6-dioxa-4-methyl-7-octensulfonic acid.
  • an active ion-exchange acidic catalyst such as Nafion-H ®
  • a sulfonated polymer prepared by polymerization of perfluorinated vinyls and perfluorinated vinyl esters, tetrafluoro-ethylene-perfluoro-3,6-dioxa-4-methyl-7-octensulfonic acid.
  • Nafion-H ® has relatively high working temperatures as compared to other polymers and is stable up to a temperature of 210 °C. It is an eco-friendly and recyclable catalyst due to the added advantages of its inertness to corrosive environments, ease of recovery and recyclable nature.
  • the catalytic activation of Nafion-H ® resin utilizes polar solvents due to increased swelling, which leads to better accessibility of the sulfonic acid active sites.
  • the acidicly enriched solid support particles are support particles of a Lewis acid, e.g. , such as silica-bound BF 3 catalyst that is believed to contain as active catalytic centers -OBF 2 and -O-B(F)-O- species (Oshidome, 2001).
  • a Lewis acid e.g. , such as silica-bound BF 3 catalyst that is believed to contain as active catalytic centers -OBF 2 and -O-B(F)-O- species (Oshidome, 2001).
  • the acidicly enriched solid support particles are support particles of an oxide, e.g ., such as those with propyl sulfonic and tosyl sulfonic acid incorporated into the amorphous silica network.
  • the acidicly enriched solid support particles are support particles of aluminosilicates or aluminophosposilicates.
  • the methods of the present invention may be utilized for the production of THC in certain devices through the conversion from CBD.
  • the devices of the present invention will be designed to operate in accordance with the methods of the present invention as described herein.
  • the devices of the present invention comprise a vessel for containing acidicly enriched solid support particles, and a plurality of CBD-activated acidicly enriched solid support particles positioned inside the vessel.
  • the devices of the present invention are well suited for use in commercial THC production or for personal THC production, and for both medical and recreational purposes.
  • the device is for medical application, e.g ., with medical precision.
  • THC tetrahydrocannabinol
  • THC tetrahydrocannabinol
  • the THC production devices of the present invention are tunable, where the THC may be selectively produced in the accelerated conversion environment.
  • the selectivity is the result of selecting the acidicly enriched solid support particles, selecting temperature, selecting time of reaction before extraction, selecting a particular solvent, or any combination thereof.
  • the selectively is produced as a single product or ratio of multiple products, e.g ., including starting material CBD.
  • the vessel is selected from the group consisting of a reaction vessel, a collection vessel, a column, a vape device, a cartridge for a vape device, a smoking device, a skin applicator, a syringe, an oral delivery device, a sublingual delivery device, and any combination thereof.
  • the vessel is selected based upon the desired use, delivery, or application, e.g ., commercial production or personal use.
  • the present invention provides methods of producing these device by introducing the CBD to a precursor device, i.e., a device prior to the introduction of CBD.
  • the vessel is selected for commercial production of THC
  • the vessel is selected for personal use production of THC.
  • the personal use production of THC is a medical device, e.g ., with medical precision control over the ratio of THC-9 and THC-8.
  • the device is programmed with a time controller to select the ratio of THC-9 and THC-8.
  • the THC production device further comprises a heating source suitable to control the temperature of vessel.
  • the heating source is a heating jacket.
  • the THC production device further comprises a means for extraction of the THC from the acidicly enriched solid support particles in the vessel.
  • the solid support particles are selected from the group consisting of acidicly enriched resin beads (e.g ., Amberlyst-15 resin beads, Nafion particles), acidicly enriched functionalized silica gel (e.g ., silica supported sulfonic and phosphoric acids), acidicly enriched zirconium oxide, acidicly enriched aluminosilicate zeolites, acidicly enriched aluminophosposilicate zeolites, and any combination thereof.
  • acidicly enriched resin beads e.g ., Amberlyst-15 resin beads, Nafion particles
  • acidicly enriched functionalized silica gel e.g ., silica supported sulfonic and phosphoric acids
  • acidicly enriched zirconium oxide e.g ., acidicly enriched aluminosilicate zeolites, acidicly enriched aluminophosposilicate zeolites, and any combination thereof.
  • the THC produced in the accelerated conversion environment is selected from the group consisting of THC-9, THC-8, and any combination thereof.
  • 500 g or greater of THC may be produced in a single use of the device (e.g., 1 kg or greater, e.g., 5 kg or greater, e.g., 10 kg or greater, e.g., 20 kg or greater, e.g., 100 kg or greater, e.g., 500 kg or greater.
  • the THC is produced with enhanced conversion efficiency of the CBD with greater than 75% efficiency (e.g., greater than 80% efficiency, e.g., greater than 85% efficiency, e.g., greater than 90% efficiency, e.g ., greater than 95% efficiency).
  • the THC produced (e.g., crude) is greater than 80% pure (e.g., greater than 85% pure, e.g., greater than 90% pure, e.g., greater than 95% pure).
  • the THC is produced at an enhanced rate (e.g.,, less than or equal to 3 hours, e.g.,, less than or equal to 2 hours, e.g. less than or equal to 1 hour, e.g., less than or equal to 45 min, e.g., less than or equal to 30 min, e.g., less than or equal to 20 min, e.g., less than or equal to 15 min, e.g., less than or equal to 10 min, e.g., less than or equal to 5 min).
  • an enhanced rate e.g., less than or equal to 3 hours, e.g.,, less than or equal to 2 hours, e.g. less than or equal to 1 hour, e.g., less than or equal to 45 min, e.g., less than or equal to 30 min, e.g., less than or equal to 20 min, e.g., less than or equal to 15 min, e.g., less than or equal to 10 min,
  • the vessel comprises a first column.
  • the device further comprises a second vessel (e.g., for a multi-column device).
  • the THC production device further comprises at least one additional column comprising a second plurality of acidicly enriched solid support particles different from the first column.
  • THC tetrahydrocannabinol
  • Another embodiment of the present invention provides a tetrahydrocannabinol (THC) production personal use device for use in producing amounts of THC that would be for ondemand use, e.g., single administration use.
  • the vessel size is selected given the desire to deliver a limited amount of THC doses for personal use.
  • THC tetrahydrocannabinol
  • the vessel is a vaping device.
  • the vessel is an oral delivery device.
  • the vessel is a sublingual delivery device.
  • the vessel comprises an extraction means to extract the THC from the acidicly enriched solid support particles, e.g ., to filter THC from catalyst and/or to stop the conversion reaction.
  • the device is tunable to selectively produce THC.
  • the device is programmed with a selected reaction time to selectively produce THC.
  • the reaction time is between 1 min and 10 min, e.g., 1 min and 5 min.
  • the device is suitable for medical precision dosing of THC.
  • the present invention has identified that the conversion of CBD to THC may be effectively catalyzed by Lewis and Br ⁇ nsted acidic catalysts on the solid support (i.e ., acidicly enriched solid support particles) with multiple advantages over the known solution chemistry.
  • the catalytic conversions of CBD and THC may be represented as follows in Scheme 1:
  • Representative catalysts from certain main groups of acidicly enriched solid support particles known in the art namely, (i) ion-exchange resins, (ii) silica and alumina oxides and (iii) aluminosilicates (zeolites) were tested (Table 1). Moreover, the functionality shown in Table 1 describes the functional groups covalently bound to the solid support particles that result in the acidic enrichment, i.e., creation of acidity, of the acidicly enriched solid support particles Table 1. Representative Br ⁇ nsted and Lewis acidicly enriched solid support particles.
  • Solid Acid Type Core Framework Acid Type Functionality Amberlyst Ion-exchange resin Organic-Polystyrene Br ⁇ nsted Toluene Sulfonic Nafion Ion-exchange resin Organic-Tetrafluoroethylene Br ⁇ nsted Fluoroalkyl sulfonic Al 2 O 3 /SO 3 H Oxide Inorganic-Al 2 O 3 Br ⁇ nsted Sulfonic SiO 2 /H 3 PO 4 Oxide Inorganic-SiO 2 Br ⁇ nsted Phosphoric SiO 2 /SO 3 H Oxide Inorganic-SiO 2 Br ⁇ nsted Alkyl-, arylsulfonic ZrO 2 /H 2 SO 4 Oxide Inorganic -ZrO 2 Lewis/Br ⁇ nsted Sulfonic, metal sites BF 3 /SiO 2 Oxide Inorganic-SiO 2 Lewis -OBF 2 Zeolites Aluminophosphosilicate Inorganic-SiO 2 /Al 2 O 3 /PO 4
  • the THC-9 may be converted into THC-9 in accordance with Scheme 2.
  • CBD powder (CBDistillery, Denver, CO, >99% purity) was dissolved in 2 ml of heptane to which 10 mg of Amberlyst-15 resin beads (dry, H + form, Dow Chemical Company; Acros Organics, Cat. No. AC202145000) have been added.
  • the reaction mixture was refluxed in a round-bottom flask equipped with a condenser for 1 h, the catalyst beads were separated by filtration and the solvent removed in the rotovap.
  • the HPLC of the reaction product revealed complete consumption of the starting CBD and formation of (-) ⁇ 8 -THC in 85 % yield.
  • a typical HPLC trace of the reaction mixture is shown in the Figure 1 .
  • the reaction had similar outcomes regarding the product yield and purity when conducted in hexane (at reflux), isopropyl myristate (IMS) at 100°C and medium chain triglycerides (100 °C, 10 h).
  • IMS isopropyl myristate
  • the higher reaction temperature was not found a prerequisite for completion in hexane or heptane with a full conversion also achieved in 48 h at ambient temperature.
  • the reaction temperatures above 100°C lead to rapid accumulation of the degradation products.
  • CBD cannabinoids and terpenes
  • the optimal amount of catalyst was found to be in the range of 5-25 % w/w to CBD.
  • reaction proceeded in various non-protic solvents and oils and could be completed in light hydrocarbons at ambient temperatures in 2 days or in accelerate mode at higher temperatures in 1-10 h.
  • hydrocarbons makes it possible for direct utilization of the reaction mixture for additional purification using Centrifugal Partitioning Chromatography (CPC) in scale up preparations of THC (Hazecamp, 2004).
  • CPC Centrifugal Partitioning Chromatography
  • CBD 50 mg was dissolved in 2 ml of heptane to which 10 mg of Nafion-SAC-13 (fluorosulfonic acid Nafion ® polymer on amorphous silica, 10-20% load, 0.6 ml/g pore volume, >10 nm pore diameter, surface are >200 m 2 /g) was added.
  • Nafion-SAC-13 fluorosulfonic acid Nafion ® polymer on amorphous silica, 10-20% load, 0.6 ml/g pore volume, >10 nm pore diameter, surface are >200 m 2 /g
  • the reaction mixture was refluxed in a round-bottom flask equipped with a condenser for 1 h, the catalyst beads were separated by filtration and the solvent removed in the rotovap.
  • the HPLC confirmed the formation of (-)- ⁇ 8 -THC as a major reaction product in 66 % yield.
  • CBD was dissolved in 2 ml of hexane to which 10 mg of SiliaBond Functionalized Silica Gel Propyl Sulfonic acid (SCX-2) or SiliaBond Tosic Acid (SCX) catalyst, both end-capped, particle size 40-60 micron, 0.6-0.8 mmol/g (SiliCycle, Quebec, Canada), were added.
  • SCX-2 SiliaBond Functionalized Silica Gel Propyl Sulfonic acid
  • SCX SiliaBond Tosic Acid
  • the CBD conversion was also almost complete in no solvent conditions by heating the melt of CBD with 10% by weight of the catalyst at 100 °C for 5 min and recovering the product by extracting the melt with hexane.
  • Silicagel catalysts provided a surprising overall acceleration of the CBD conversion (>10x) compared to Amberlyst, Nafion and BF 3 /SiO 2 . Also silicagels allowed substantial stabilization of the THC-9 isomer in a convenient adaptation of the reaction at room temperature. Three other tested solid catalysts showed intermittent formation THC-9 only at early reaction time points corresponding to very low conversion of CBD and thus bearing little practical utility as an approach to THC-9.
  • the acidicly enriched solid support particles are not Al 2 O 3 acidic or NaHSO 4 . In certain embodiments, the acidicly enriched solid support particles are not ZrO 2 H 2 SO 4 .
  • aluminosilicates and aluminophosposilicates act as very efficient catalysts of the CBD-to-THC conversion at loads of 10-50 %.
  • the tested materials are listed in Table 3. In these embodiments, it was essential to have the catalyst in the H+ form. When in the salt form (shown for Zeolite Y), the materials were found to be inactive. Table 4.
  • the acidicly enriched solid support particles are not SAPO-34. In certain embodiments, the acidicly enriched solid support particles are not ZSM-5.
  • the reaction proceeds with high conversion outcomes in refluxed heptane over a period of 1 h. Surprisingly, the transformation is significantly accelerated when conducted in the melt, without any solvent. Using aluminosilicates helps to stabilize THC-9 vs. THC-8 reaction products. In only 5 minutes time, the conversion rate was already about 80% with THC-9/THC-8 ratio of 2:1.
  • the outcomes of catalytic transformations in different reaction conditions for the most active materials, i.e., Zeolite Y, SAPO-11 and Zeolite Beta are summarized in the Tables 5-7. Table 5.
  • Reaction Products of CBD-to-THC Conversion Catalyzed by Aluminophosphosilicate SAPO-11 Composition of Reaction Products Reaction Conditions (Time, Temperature, Solvent) 5 min, Reflux Heptane 30 min, Reflux Heptane 60 min, Reflux Hexane 5 min, Reflux Hexane 5 min, 100°C Solid CBD, % 72 27 2 20 2 THC-9, % 21 43 45 46 31 THC-8, % 2 14 23 22 35 Table 6.

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Claims (20)

  1. Procédé économe en matériaux pour la conversion de cannabidiol (CBD) en tétrahydrocannabinol (THC) comprenant l'étape de :
    introduction de CBD dans ou sur des particules de support solide enrichies de façon acide comprenant des groupes fonctionnels acides qui sont liés de façon covalente aux particules de support solide, pour créer un environnement de conversion accélérée activé par CBD,
    de sorte que du THC est produit.
  2. Procédé économe en matériaux selon la revendication 1, dans lequel les particules de support solide sont choisies dans le groupe constitué de billes de résine enrichies de façon acide, gel de silice fonctionnalisé enrichi de façon acide, oxyde de zirconium enrichi de façon acide, zéolites d'aluminosilicate enrichies de façon acide, zéolites d'aluminophosposilicate enrichies de façon acide, et une combinaison quelconque de ceux-ci.
  3. Procédé économe en matériaux selon la revendication 1 ou 2, comprenant en outre l'étape de chauffage dudit environnement de conversion accélérée activé par CBD.
  4. Procédé économe en matériaux selon la revendication 3, dans lequel l'environnement de conversion accélérée est chauffé à une température inférieure ou égale à 100 °C.
  5. Procédé économe en matériaux selon l'une quelconque des revendications 1, 2, 3 ou 4, dans lequel l'étape d'introduction du CBD dans les particules de support solide enrichies de façon acide est effectuée par dissolution dans un solvant du CBD pour créer l'environnement de conversion accélérée activé par CBD.
  6. Procédé économe en matériaux selon l'une quelconque des revendications 1, 2, 3 ou 4, dans lequel l'étape d'introduction du CBD dans les particules de support solide enrichies de façon acide est effectuée par fusion directe sans solvant du CBD pour créer l'environnement de conversion accélérée activé par CBD.
  7. Procédé économe en matériaux selon l'une quelconque des revendications 1, 2, 3, 4, 5 ou 6, comprenant en outre l'étape d'extraction des particules de support solide.
  8. Procédé économe en matériaux selon l'une quelconque des revendications 1, 2, 3, 4, 5, 6 ou 7, dans lequel le THC produit dans l'environnement de conversion accélérée est choisi dans le groupe constitué de THC-9, THC-8, et une combinaison quelconque de ceux-ci.
  9. Procédé économe en matériaux selon la revendication 8, dans lequel le THC est sélectivement produit dans l'environnement de conversion accélérée.
  10. Procédé économe en matériaux selon la revendication 8 ou 9, dans lequel le THC produit dans l'environnement de conversion accélérée est enrichi en THC-9.
  11. Procédé économe en matériaux selon la revendication 8 ou 9, dans lequel le THC produit dans l'environnement de conversion accélérée est enrichi en THC-8.
  12. Procédé sans solvant pour la conversion de cannabidiol (CBD) en tétrahydrocannabinol (THC) comprenant l'étape de :
    introduction de CBD dans ou sur des particules de support solide enrichies de façon acide comprenant des groupes fonctionnels acides qui sont liés de façon covalente aux particules de support solide, par fusion directe du CBD pour créer un environnement de conversion accélérée activé par CBD, de sorte que du THC est produit.
  13. Dispositif de production de tétrahydrocannabinol (THC) comprenant :
    une cuve pour contenir des particules de support solide enrichies de façon acide ; et
    une pluralité de particules de support solide enrichies de façon acide activées par CBD positionnées à l'intérieur de la cuve dans ou sur lesquelles du CBD a été introduit, dans lequel du THC est produit à partir des particules de support solide enrichies de façon acide activées par CBD, dans lequel les particules de support solide enrichies de façon acide comprennent des groupes fonctionnels acides qui sont liés de façon covalente au support solide.
  14. Dispositif de production de THC selon la revendication 13, dans lequel la cuve est choisie dans le groupe constitué d'une cuve de réaction, une cuve de collecte, une colonne, un dispositif de vapotage, une cartouche pour un dispositif de vapotage, un dispositif pour fumer, un applicateur cutané, une seringue, et une combinaison quelconque de ceux-ci.
  15. Dispositif de production de THC selon la revendication 13 ou 14, dans lequel la cuve est choisie pour la production commerciale de THC, dans lequel 500 g ou plus de THC peuvent être produits dans une seule utilisation du dispositif.
  16. Dispositif de production de THC selon la revendication 13 ou 14, dans lequel la cuve est choisie pour la production de THC pour usage personnel pour délivrer une quantité limitée de THC pour usage personnel.
  17. Dispositif de production de THC selon l'une quelconque des revendications 13, 14, 15 ou 16, comprenant en outre une source de chauffage adaptée pour réguler la température de cuve.
  18. Dispositif de production de THC selon l'une quelconque des revendications 13, 14, 15, 16 ou 17, dans lequel les particules de support solide sont choisies dans le groupe constitué de billes de résine enrichies de façon acide, gel de silice fonctionnalisé enrichi de façon acide, oxyde de zirconium enrichi de façon acide, zéolites d'aluminosilicate enrichies de façon acide, zéolites d'aluminophosposilicate enrichies de façon acide, et une combinaison quelconque de ceux-ci.
  19. Dispositif de production de THC selon l'une quelconque des revendications 13, 14, 15, 16, 17 ou 18, dans lequel le THC produit dans l'environnement de conversion accélérée est choisi dans le groupe constitué de THC-9, THC-8, et une combinaison quelconque de ceux-ci.
  20. Dispositif de production de THC selon l'une quelconque des revendications 13, 14, 15, 16, 17, 18 ou 19, dans lequel le THC est ajustable, et le dispositif étant programmé avec une durée de réaction choisie pour produire sélectivement le THC dans l'environnement de conversion accélérée.
EP20738382.9A 2019-01-11 2020-01-13 Méthode et dispositif associé pour la conversion de cbd en thc Active EP3908273B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201962791122P 2019-01-11 2019-01-11
PCT/US2020/013418 WO2020146907A1 (fr) 2019-01-11 2020-01-13 Nouvelles méthodes et outils associés pour conversion de cbd en thc

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PE20212268A1 (es) * 2019-01-11 2021-11-30 Arielium Health Llc Metodos novedosos y herramientas relacionadas para la conversion de cbd en thc
CA3135650A1 (fr) * 2019-04-05 2020-10-08 Rapid Dose Therapeutics Corp. Appareil et procede pour convertir un cbd et/ou des derives de cbd en au moins un autre type de cannabinoide et/ou de derive de cannabinoide tel que le thc
EP3983395A4 (fr) * 2019-06-11 2023-10-18 Canopy Growth Corporation Procédés améliorés de conversion de cannabidiol en delta 8-tétrahydrocannabinol
EP3983396A4 (fr) * 2019-06-11 2023-05-10 Canopy Growth Corporation Procédés améliorés de conversion de cannabidiol en delta9-tétrahydrocannabinol dans des conditions de réaction pures ou aprotiques
US10941131B1 (en) * 2019-10-28 2021-03-09 Pure Tonic Concentrates, LLC Conversion of cannabidiol or delta-9 tetrahydrocannabinolic acid to delta-9 tetrahydrocannabinol and delta-8 tetrahydrocannabinol in nontoxic heterogeneous mixtures
WO2021207605A1 (fr) * 2020-04-10 2021-10-14 3Bc, Llc Procédés de préparation de cannabinoïdes et instruments associés
CA3132439A1 (fr) 2020-05-12 2021-11-12 Canopy Growth Corporation Methodes de synthese du cannabigerole, de l`acide cannabigerolique et d`analogues connexes
CN112661739A (zh) * 2020-12-30 2021-04-16 福建省中科生物股份有限公司 一种萜酚类化合物及其与顺铂联用在抗肿瘤医药上的用途
CN117603177A (zh) * 2023-09-28 2024-02-27 中国农业科学院麻类研究所 固体酸催化剂、大麻二酚转化为δ8-四氢大麻酚的方法
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WO2002070506A2 (fr) * 2001-03-07 2002-09-12 Websar Innovations Inc. Conversion de cbd en $g(d)8-thc et en $g(d)9-thc
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US12264141B2 (en) 2025-04-01
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US20250223273A1 (en) 2025-07-10
PE20212268A1 (es) 2021-11-30
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AU2020207418B2 (en) 2024-01-18
CN113631162A (zh) 2021-11-09
AU2020207418A1 (en) 2021-08-26
EP3908273A4 (fr) 2022-08-31
IL284702B1 (en) 2025-03-01
US20200223814A1 (en) 2020-07-16
CA3114611C (fr) 2022-12-06
MA54708A (fr) 2022-03-16
EP3908273C0 (fr) 2024-03-27
MX2021008439A (es) 2021-10-13
IL284702A (en) 2021-08-31
ES2981363T3 (es) 2024-10-08
US11098024B2 (en) 2021-08-24
WO2020146907A1 (fr) 2020-07-16
NZ778873A (en) 2025-08-29
US20210363125A1 (en) 2021-11-25
CL2021001842A1 (es) 2022-04-01
CR20210425A (es) 2021-12-06
CA3114611A1 (fr) 2020-07-16

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